Summary Polygenic risk scores have the potential to change management for common diseases. However, concerns exist about the clinical implementation of PRS including the likely decreased performance of PRS in non-white populations and the need to develop improved communication and extended informatics support for use of the PRS in health care decisions. At Northwestern we will address these concerns through three major scientific questions related to the clinical use of PRS: 1) Does use of PRS contribute to improved adherence to risk management strategies and improved clinical outcomes? 2) Does a high risk PRS presented with culturally sensitive and tailored risk communication improve adherence and outcomes across diverse racial and ethnic groups? 3) Can we develop and test information technology that stores PRS in the EHR and delivers clinical decision support (CDS) to aid providers in PRS use clinically? To enable recruitment, retention, and outcome monitoring, we will create and then disseminate a smartphone application across Northwestern and, as possible, the Electronic Medical Records and Genomics (eMERGE) network to facilitate the goals of eMERGE 4 (e4). Northwestern has been a primary contributor to all phases of eMERGE with Northwestern investigators holding key leadership roles in the network. Northwestern?s previous rich experience in electronic phenotyping involves using information extracted from our enterprise data warehouse, along with genomics and epidemiology expertise in many areas, including PRS, for genomic discovery projects. We have a demonstrated ability to recruit and retain large and ethnically diverse clinical populations for genetic result return, and repeated successful integration of genetic results into Northwestern?s electronic health record as discrete, computable lab values enabling effective clinical decision support. We will employ innovative enrollment techniques that have higher success rates in diverse populations. As participants in the e4 consortium we will implement a program called ENDORSED (eMERGE Northwestern Develops Optimized Risk Scores for Everyone?s DNA). Through the following aims ENDORSED will assess the utility of PRS, including in diverse populations. In Aim 1, we will calculate and validate PRS for common disorders selected specifically because they have medically-actionable outcomes. Aim 2 will recruit 2500 subjects for participation in eMERGE 4, taking advantage of Northwestern Medicine?s extensive clinical network. Aim 3 will use behavior theory to create culturally sensitive communication tools and then integrate PRS data into the electronic health record. Aim 4 will then examine outcomes and uptake of behaviors before and after PRS return. The completion of these aims will assess and evaluate PRS use for common diseases in diverse groups producing important data about real-world implementation of genomic medicine.